Judicious application of allyl protecting groups for the synthesis of 2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl triflate, a key precursor of DNA-dependent protein kinase inhibitors

Article abstract of DOI:10.1021/ol062297x

(Chemical Equation Presented) 2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl 2,2,2-trifluoromethanesulfonate is a key intermediate for the synthesis of the DNA-dependent protein kinase (DNA-PK) inhibitor 8-dibenzothiophen-4-yl-2- morpholin-4-yl-chromen-4-one (NU7441). Two improved methods for the synthesis of this triflate have been developed: (A) in 35% overall yield, through modification of the published route, and (B) in 15% overall yield, by a new route employing a Baker-Venkataraman rearrangement to enable generation of the chromenone scaffold. Both syntheses depend on the judicious use of allyl protecting groups.

Full text of DOI:10.1021/ol062297x

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5927-5929
Judicious Application of Allyl Protecting
Groups for the Synthesis of
2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl
Triflate, a Key Precursor of
DNA-Dependent Protein Kinase
Inhibitors
Sonsoles Rodriguez Aristegui, Marine Desage El-Murr, Bernard T. Golding,*
Roger J. Griffin, and Ian R. Hardcastle*
Northern Institute for Cancer Research, School of Natural Sciences - Chemistry,
Bedson Building, Newcastle UniVersity, Newcastle upon Tyne NE1 7RU, U.K.
b.t.golding@ncl.ac.uk; i.r.hardcastle@ncl.ac.uk
Received September 19, 2006
ABSTRACT
2-Morpholin-4-yl-4-oxo-4H-chromen-8-yl 2,2,2-trifluoromethanesulfonate is a key intermediate for the synthesis of the DNA-dependent protein
kinase (DNA-PK) inhibitor 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441). Two improved methods for the synthesis of this
triflate have been developed: (A) in 35% overall yield, through modification of the published route, and (B) in 15% overall yield, by a new route
employing a Baker−Venkataraman rearrangement to enable generation of the chromenone scaffold. Both syntheses depend on the judicious
use of allyl protecting groups.
DNA-dependent protein kinase (DNA-PK) is a nuclear serine/
threonine kinase, which is activated by DNA double-strand
breaks.1 Inhibition of DNA-PK with ATP-competitive, small
molecules potentiates DNA-damaging agents, such as ioniz-
ing radiation or alkylating agents, which are commonly used
in cancer therapy.2 We have reported potent, selective DNA-
PK inhibitors based on a chromen-4-one scaffold, notably
8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
(NU7441, IC50 ) 12 nM),3,4 prepared via a Suzuki-Miyaura
coupling between 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl
triflate (1) and 4-dibenzothiophene boronic acid (Scheme 1).
(2) Zhao, Y.; Thomas, H. D.; Batey, M. A.; Cowell, I. G.; Richardson,
C. J.; Griffin, R. J.; Calvert, A. H.; Newell, D. R.; Smith, G. C. M.; Curtin,
N. J. Cancer Res. 2006, 66, 5354-5362.
(3) Leahy, J. J. J.; Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.;
Richardson, C.; Rigoreau, L.; Smith, G. C. M. Bioorg. Med. Chem. Lett.
2004, 14, 6083-6087.
(1) Smith, G. C. M.; Jackson, S. P. Genes DeV. 1999, 13, 916-934.
10.1021/ol062297x CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/18/2006

Scheme 1. Synthesis of 8-Dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441)3
The synthesis of triflate 1 was achieved in three steps from
by Tsuritani et al.,10 the selectivity results from the TiCl4
coordinating to the keto group, preferentially activating the
ortho-allyl group to nucleophilic displacement by iodide.
Selective protection of the 3-hydroxyl group of 2,3-
dihydroxybenzaldehyde with allyl or benzyl has been
reported.11,12 However, the yield for allylation was 48%,11
compared to the 86% or 89% overall yield obtained for the
protection-deprotection sequence (Scheme 2). Although
73% was claimed for selective benzylation of 2,3-dihydroxy-
benzaldehyde at the 3-hydroxyl group,12 in our hands only
27% was achieved.
An alternative route to 1 started with bisallyl protection
of aldehyde 10, giving 11 in excellent yield. Compound 11
was converted into the corresponding methyl ketone 12, in
70% yield over two steps, by treatment with MeMgBr,
followed by oxidation of the intermediate alcohol using
pyridinium chlorochromate. Selective deprotection of one
allyl group proceeded as described above, giving the ac-
etophenone derivative 13. Reaction of 13 with morpholine
N-chloroformate gave the carbamate 14 in good yield.
Baker-Venkataraman rearrangement of 14 was achieved by
treatment with potassium hydroxide in pyridine, to give the
ketoamide 7 in good yield.
Ring closure of 7 to the 8-allyloxy chromenone 8 was
effected by treatment with triflic anhydride in DCM.13
Removal of the O-allyl protecting group by a two-step
procedure of isomerization to an O-propenyl intermediate
effected by a suitable catalyst (e.g., Wilkinson’s catalyst
[RhCl(PPh3)3];14 ruthenium-based catalysts15,16), followed by
mild acidic hydrolysis of the propenyl group to release
hydroxyl, has often been reported. We have found that
treatment of 8 with Wilkinson’s catalyst and 1,4-diazabicyclo-
[2.2.2]octane (DABCO) in EtOH gave 8-hydroxychromenone
9 directly in 93% yield, obviating the need for an acidic
cleavage step. A limited study of the scope of this simplified
method for removing allyl has shown that, for example, 15
can be deprotected to 16 in excellent yield (Scheme 3).
Finally, compound 9 was converted into 1 using N-phenyl-
triflimide and triethylamine.
methyl 2,3-dihydroxybenzoate (2) but in a poor overall yield
(4%, Scheme 1).3,4 There were problems with each step of
this route: lack of selectivity in the conversion of ester 2
into 3, a byproduct (di-O-triflate) being obtained in signifi-
cant yield; the requirement for more than 2 equiv of the
lithium enolate of N-acetylmorpholine, because of the
deprotonation of the phenolic hydroxyl group of 3; and the
poor yield of 1 from the cyclization of ketoamide 4.
As part of an ongoing program of optimization of DNA-
PK inhibitors, we sought a more efficient route to 1. On the
basis of the premise that the cyclization of ketoamide 4 was
impeded by the triflate group, replacement by the electron-
releasing O-allyl group was regarded as potentially advanta-
geous. Allyl was also chosen because of its stability under
the strongly acidic and basic conditions required and its
ability to be removed under specific conditions.5 We envis-
aged that the intermediate allyl-protected ketoamide 7
(Scheme 2) could be accessed by two routes. One was a
modification of the existing route to 4,3 and the other
exploited the Baker-Venkataraman rearrangement.6 Cy-
clization of 7, followed by removal of the allyl protecting
group and conversion of the liberated hydroxyl group into a
triflate ester, would give the desired 1.
Allyl protection of both hydroxyl groups in ester 2 was
achieved in excellent yield under standard conditions7 giving
5. Reaction of 5 with the lithium enolate of N-acetylmor-
pholine gave ketoamide 6 in much improved yield (cf.
Schemes 1 and 2). To remove the allyl group ortho to the
carbonyl function of 6, palladium catalysis8 and DDQ9 were
initially tried. However, Pd removed both allyl groups from
6, and DDQ gave unreacted starting material. The reagent
TiCl4/Bu4NI has been reported for the selective monodepro-
tection of diprenyl ethers.10 We found that TiCl4/Bu4NI
accomplished selective deprotection of the ortho-allyl group
of 6 to give phenol 7 in near quantitative yield. As suggested
(4) Hardcastle, I. R.; Cockcroft, X.; Curtin, N. J.; El-Murr, M. D.; Leahy,
J. J. J.; Stockley, M.; Golding, B. T.; Rigoreau, L.; Richardson, C.; Smith,
G. C. M.; Griffin, R. J. J. Med. Chem. 2005, 48, 7829-7846.
(5) Guibe, F. Tetrahedron 1998, 54, 2967-3042.
(6) Kraus, G. A.; Fulton, B. S.; Wood, S. H J. Org. Chem. 1984, 49,
3212-3114.
(11) Kilenyi, S. N.; Mahaux, J. M.; Durme, E. V. J. Org. Chem. 1991,
56, 2591-2594.
(12) Parker, K. A.; Georges, A. T. Org. Lett. 2000, 2, 497-499.
(13) Morris, J.; Wishka, D.; Fang, Y. Synth. Commun. 1994, 24, 849-
858.
(14) Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973, 38, 3224-3224.
(15) Cadot, C.; Dalko, P. I.; Cossy, J. Tetrahedron Lett. 2002, 43, 1839-
1841 and 5205.
(7) Van, T. N.; Debenedetti, S.; De Kinpe, N. Tetrahedron Lett. 2003,
44, 4199-4201.
(8) Vutukuri, D. R.; Bharathi, P.; Yu, Z.; Rajasekaran, K.; Tran, M.-H.;
Thayumanavan, S. J. Org. Chem. 2003, 68, 1146-1149.
(9) Yadav, J. S.; Chandrasekhar, S.; Sumithra, G.; Kache, R. Tetrahedron
Lett. 1996, 37, 6603-6606.
(10) Tsuritani, T.; Shinokubo, H.; Oshima, K. Tetrahedron Lett. 1999,
40, 8121-8124.
(16) Tanaka, S.; Saburi, H.; Kitamura, M. AdV. Synth. Catal. 2006, 348,
375-378.
5928
Org. Lett., Vol. 8, No. 26, 2006

Scheme 2. Synthesis of Triflate 1 from Ester 5a or Aldehyde 10b
b
a 35% overall yield. 15% overall yield.
Comparison of the three methods described for the
synthesis of triflate 1 shows that the published method4 has
the advantage of being the shortest (three steps) but has an
nine straightforward steps, affording 1 in 15% overall yield.
Modification of the original route4 by judicious protection-
deprotection of hydroxyl groups with allyl represented a
significant improvement in overall yield (35%). The three
extra steps required were all trivial and high yielding.
Scheme 3. Rh-Mediated Deprotection of 15
Acknowledgment. The authors thank Cancer Research
UK and KuDOS Pharmaceuticals Ltd. for funding and the
EPSRC Mass Spectrometry Service at The University of
Wales, Swansea, U.K.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
unacceptable, very poor overall yield of just 4%. The Baker-
Venkataraman route gave acceptable yields throughout over
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